Persistent vulnerability to relapse is a major obstacle in the clinical treatment of drug addiction. The goal of this proposal is to understand the neural mechanisms that control drug-seeking behavior, with specific reference to excitatory synaptic plasticity in the nucleus accumbens (NAc). In animal models of addiction, NAc glutamate transmission has been clearly implicated in both extinction and reinstatement of drug seeking behavior. We propose to use whole-cell patch-clamp electrophysiology in acute brain slices from mice run through a place conditioning paradigm, to study the relationship between excitatory synaptic function in NAc and the extinction and reinstatement of conditioned cocaine reward. Our preliminary studies demonstrate the feasibility of this approach, and also support a relationship between NAc synaptic strength and reinstatement. We will use the flexibility of the place conditioning paradigm to study both decreases (extinction) and increases (reinstatement) in drug-seeking behavior. We predict that reinstatement involves reduced NAc synaptic strength, and that blocking this reduction will prevent reinstatement behavior. Conversely, we expect that extinction will enhance NAc synaptic strength, and this change will be accelerated when animals are given D-cycloserine - a partial NMDA receptor agonist known to facilitate extinction. These experiments present a unique opportunity to study the relationship between synaptic plasticity and behavior in a situation where each can be-bidirectionally modulated. The results will guide the development of therapeutic interventions targeted at glutamate transmission that can reduce vulnerability to relapse in human drug addicts. PUBLIC HEALTH RELEVANCE: Drug addiction is a major public health problem that is perpetuated when former drug addicts relapse to using drugs again. This research will help us understand changes in brain function caused by drug use that leave addicts vulnerable to relapse. It will also examine how brain function might be modified to reduce the pursuit of drugs.